1 alpha,25-Dihydroxyvitamin D3 (1 alpha,25-(OH)2D3) is a sterol formed in the kidney which is the hormonal form of vitamin D. Studies will be directed toward elucidating the molecular mode of action of 1 alpha,25-(OH)2D3 in stimulating calcium transport across the intestine. Cytoplasmic and nuclear receptors for the hormone will be further isolated and characterized in terms of their interrelationship, and the effects of the chromatin bound-nuclear form on template efficiency and RNA polymerase activity will be examined to delineate how the hormone may be altering DNA transcription. A second objective will be the clarification of the endocrine loops which regulate the secretion of 1 alpha,25-(OH)2D3 from the kidney. A comprehensive investigation of the physiologic and pharmacologic factors which control the biosynthesis and circulating level of this hormone will be performed using radioreceptor assay. Special attention will be paid to pituitary, gonadal, and other humoral factors which may regulate 1 alpha,25-(OH)2D3 production during physiologic situations of calcium stress. Finally we plan to use the radioreceptor assay for 1 alpha,25-(OH)2D in humans to study further the possible involvement of this hormone in the pathophysiology of metabolic bone diseases.